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A novel BH3 mimetic S1 potently induces Bax/Bak‐dependent apoptosis by targeting both Bcl‐2 and Mcl‐1
Author(s) -
Zhang Zhichao,
Song Ting,
Zhang Tiantai,
Gao Jin,
Wu Guiye,
An Lijia,
Du Guanhua
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25484
Subject(s) - apoptosis , small hairpin rna , small molecule , cancer research , microbiology and biotechnology , immunoprecipitation , chemistry , biology , cell culture , biochemistry , genetics , gene knockdown
Broad spectrum Bcl‐2 small molecule inhibitors act as BH3 mimetics are effective antitumor agents. Herein, we have identified S1 , a previously discovered small molecule Bcl‐2 inhibitor, as the first authentic BH3 mimetic as well as a dual, nanomolar inhibitor of Bcl‐2 and Mcl‐1 ( K i = 310 nM and 58 nM, respectively). The results of fluorescence polarization assays, coimmunoprecipitation, fluorescent resonance energy transfer, and shRNA indicated that S1 can disrupt Bcl‐2/Bax, Mcl‐1/Bak and Bcl‐2/Bim heterodimerization in multiple cell lines, activate Bax accompanied by its translocation to mitochondrial, activate caspase 3 completely dependent on Bax/Bak, and in turn induce a Bim‐independent apoptosis. Moreover, S1 could induce apoptosis on the primary acute lymphoblastic leukemia cells regardless of Mcl‐1 level. Mechanism‐based single agent antitumor activity in a mouse xenograft H22 (mouse liver carcinoma) model ascertain its therapeutic potential. S1 represents a novel chemical class of antitumor leads that function solely as BH3 mimetics and pan‐Bcl‐2 inhibitors. In the meanwhile, S1 could become a unique tool for interactions between Bcl‐2 family proteins.